Andappan et al.
with HCl (5 M, 2 mL) for 1 h and subsequently partitioned
between ethyl acetate and H O. The organic layer was washed
with water and brine, dried over anhydrous MgSO , and
concentrated in vacuo to afford the crude product, which was
purified by centrifugal chromatography (ethyl acetate in
hexane, silica gel 60) or bulb-to-bulb distillation to afford the
pure product 4.
and dmphen (0.022 g, 0.100 mmol) in EtCN (1.0 mL) was
stirred for 10 min (color change from brown to yellow), and
the yellow suspension was transferred into a Smith vial (32
mL) containing 4-methylphenylboronic acid (1d ; 0.28 g, 2.0
mmol), N-vinylpyrrolidinone (5; 0.11 g, 1.0 mmol), and N-
methylmorpholine (0.22 mL, 2.0 mmol) in EtCN (7.0 mL). The
vial was flushed with oxygen gas, capped, and then pressurized
with oxygen gas through a sharp needle attached to the oxygen
cylinder tube (ca. 3 bar on the basis of the pressure gauge
readings of the oxygen cylinder). The vial was then heated at
100 °C for 1 h in the microwave synthesizer, cooled to room
temperature, and uncapped. The reaction mixture was there-
2
4
Gen er a l P r otocol for In ter n a l Ar yla tion of Acyclic
En a m id es a n d Isola tion of 8-10, Ta ble 2. A mixture of Pd-
2
(OAc) (0.020 or 0.040 mmol) and 2,9-dimethyl-1,10-phenan-
throline (0.024 or 0.048 mmol) in 1,4-dioxane (0.5 mL) was
stirred for 15 min at 50 °C in a round-bottomed flask. To this
suspension, which had turned yellow, were successively added
arylboronic acid (2.0 mmol), N-methylmorpholine (0.22 mL,
after partitioned between ethyl acetate and H
layer was washed with water and brine, dried over anhydrous
MgSO , and concentrated in vacuo to afford the crude product,
2
O. The organic
2
.0 mmol), enamide 5, 6, or 7 (1.0 mmol), and 1,4-dioxane (2.0
4
mL). The oxygen-filled balloon was then attached atop and the
mixture vigorously stirred at the specified temperature and
time. After cooling to room temperature, the balloon was
removed, the mixture was diluted with water and ethyl
acetate, and the contents were transferred into a separatory
funnel. The flask was washed further with ethyl acetate. After
the addition of more ethyl acetate and water, the layers were
separated. The organic layer was washed with water and
which was purified by centrifugal chromatography (20% ethyl
acetate in hexane, silica gel 60) to afford the pure product 8d
as a light-yellow oil (0.161 g, 80%).
(B) La r ge Sca le in a Mu ltip le-Mod e Micr ow a ve Ba tch
2
Rea ctor . A mixture of Pd(OAc) (0.112 g, 0.500 mmol) and
dmphen (0.217 g, 1.00 mmol) in EtCN (5.0 mL) was stirred
for 10 min (color change from brown to yellow) and subse-
quently transferred into a Teflon vessel (350 mL) containing
1d (2.8 g, 20 mmol), 5 (1.10 g, 10 mmol), and N-methylmor-
pholine (2.2 mL, 20 mmol) in EtCN (75 mL). The vessel was
attached to the flange, the autoclave was closed, and oxygen
was supplied through the gas inlet from the oxygen cylinder.
The oxygen pressure was maintained at ca. 3 bar throughout,
while the temperature was monitored by a fiber-optic ther-
mometer inserted inside the reactor vessel. The stirring
reaction mixture was then heated at 80 °C for 70 min in the
microwave synthesizer (Emrys Advancer), and thereafter
cooled to room temperature. The autoclave was opened, and
the reaction mixture was stirred with dilute HCl (5 M, 30 mL)
for 1 h. The reaction mixture was subsequently partitioned
4
brine, dried over anhydrous MgSO , and concentrated in vacuo.
The residue was purified by centrifugal chromatography using
hexane or a mixture of hexane and ethyl acetate as eluent to
afford the pure enamide product.
Gen er a l P r oced u r e for Ar yla tion of En a m id es 5-7 a n d
2
Isola tion of 4, Ta ble 2. A mixture of Pd(OAc) (0.020 or 0.040
mmol) and 2,9-dimethyl-1,10-phenanthroline (0.024 or 0.048
mmol) in 1,4-dioxane (0.5 mL) was stirred for 15 min at 50 °C
(see Table 2 for further details regarding amount of catalyst
and temperature). To this suspension, which had turned
yellow, were successively added arylboronic acid (2.0 mmol),
N-methylmorpholine (0.22 mL, 2.0 mmol), enamide 5, 6, or 7
(
1.0 mmol), and 1,4-dioxane (2.0 mL). The oxygen-filled balloon
between ethyl acetate (250 mL) and H
layer was separated, washed with water and brine, dried over
anhydrous MgSO , and concentrated in vacuo to afford the
crude product, which was purified by centrifugal chromatog-
raphy (2% ethyl acetate in hexane, silica gel 60) to afford the
pure ketone 4d as a light-yellow oil (0.885 g, 66%).
2
O (250 mL). The organic
was then attached atop and the mixture vigorously stirred at
the specified temperature and time. After cooling to room
temperature, the balloon was removed and the mixture diluted
with HCl (5 M, 2 mL) for 1 h and subsequently partitioned
between ethyl acetate and H
with water and brine, dried over anhydrous MgSO
4
2
O. The organic layer was washed
4
, and
Ack n ow led gm en t. We acknowledge the financial
support from the Swedish Research Council and from
Knut and Alice Wallenberg’s Foundation. We also thank
Biotage AB for providing us with the EmrysOptimizer
EXP and EmrysAdvancer. Parallelldatorcentrum (PDC)
at the Royal Institute of Technology is acknowledged
for providing computer facilities. Finally, we thank Prof.
Anders Hallberg, Prof. Åke Pilotti, and Mr. Shane
Peterson for intellectual contributions to this project.
concentrated in vacuo to afford the crude product, which was
purified by centrifugal chromatography (ethyl acetate in
hexane, silica gel 60) or bulb-to-bulb distillation to afford the
pure product 4.
N-(1-[4-Meth oxyp h en yl]eth en yl)-2-p yr r olid in on e (8a ).
The residue was purified by centrifugal chromatography (silica
gel 60, 50% ethyl acetate in hexane) to afford the title product
1
as a colorless liquid (0.171 g, 79%). H NMR (400 MHz,
CDCl
3
): δ 2.10 (m, 2H), 2.56 (t, 2H, J ) 8.1 Hz), 3.54 (t, 2H,
J ) 7.0 Hz), 3.81 (s, 3H), 6.86 (m, 2H), 6.86 (m, 2H), 7.26 (m,
1
3
2
1
1
1
H). C NMR (100 MHz, CDCl
3
): δ 18.6, 31.9, 49.6, 55.3,
):
701 cm . MS: m/z (relative intensity) 217 (M , 100), 174 (58),
33 (21). HRMS (FAB+): m/z calcd for {C13 } 217.1103,
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for all new compounds, computa-
tional details, and energies and Cartesian coordinates of all
investigated structures (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
08.0, 113.8, 127.6, 128.6, 143.1, 159.8, 174.6. (IR, CDCl
3
-1
+
H
15NO
2
found 217.1103
Micr ow a ve Exp er im en ts. (A) Sm a ll Sca le in a Sin gle-
Mod e Rea ctor . A mixture of Pd(OAc) (0.011 g, 0.050 mmol)
2
J O049434T
5
218 J . Org. Chem., Vol. 69, No. 16, 2004